This invention belongs to the fields of pharmaceutical chemistry and synthetic organic chemistry, and provides an asymmetric process for the synthesis of a key intermediate in the preparation of duloxetine, (+)-N-methyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine, hydrochloric acid salt.
Duloxetine is a pharmaceutical now under development as an anti-depressant. It inhibits the uptake of both norepinephrine and serotonin and is presently in clinical evaluation. The compound was disclosed in U.S. Pat. Nos. 5,023,269 and 4,956,388 by Robertson, et al., and the synthesis of it was discussed in more detail by Deeter, et al., in Tetrahedron Letters, 31(49), 7101-04 (1990). The process for preparing duloxetine is there outlined as follows. ##STR1##
The product of Step D above, when in the hydrochloride salt form, is duloxetine.
The present invention provides improved conditions for carrying out Step C in the above scheme, whereby the product of Step C is obtained more quickly in better purity and yield than has previously been possible.
A particularly useful salt for the isolation of the intermediate is also provided.